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Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients
  1. I Trender-Gerhard1,
  2. M G Sweeney2,
  3. P Schwingenschuh1,3,
  4. P Mir1,4,
  5. M J Edwards1,
  6. A Gerhard5,
  7. J M Polke2,
  8. M G Hanna6,
  9. M B Davis2,
  10. N W Wood2,
  11. K P Bhatia1
  1. 1
    Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London, UK
  2. 2
    Department of Molecular Neuroscience, Institute of Neurology, London, UK
  3. 3
    Department of Neurology, Medical University Graz, Austria
  4. 4
    Unidad de Trastornos del Movimiento, Servicio de Neurología, Hospitales Universitarios Virgen del Rocío, CIBERNED, Seville, Spain
  5. 5
    Wolfson Molecular Imaging Centre, The University of Manchester, Manchester, UK
  6. 6
    MRC Centre for Neuromuscular Disease, Institute of Neurology, London, UK
  1. Professor K P Bhatia, Sobell Department, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK; k.bhatia{at}


Background: An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower-limb dystonia, diurnal fluctuations and excellent response to levodopa has been well recognised in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow-up of genetically proven cases.

Methods: A detailed clinical evaluation of 34 patients (19 women, 15 men), with confirmed mutations in the GCH1 gene, is presented.

Results and conclusions: The classic phenotype was most frequent (n = 23), with female predominance (F:M = 16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n = 4), or with an adult-onset (mean 37 years) Parkinson disease-like phenotype (n = 4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. The study also describes a number of supplementary features including restless-legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder and specific levodopa-resistant symptoms (writer’s cramp, dysphonia, truncal dystonia). Levodopa was used effectively and safely in 20 pregnancies, and did not cause any fetal abnormalities.

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  • Competing interests: None.

  • Ethics approval: Ethics approval was provided by Joint Research Ethics Committee of the Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK.

  • Patient consent: Obtained.